PROJECT SUMMARY/ABSTRACT Fibrocartilage tears in the avascular white-white zone of the meniscus are a significant clinical challenges due to their inability to heal. These common injuries are independent risk factors for the development of post-traumatic osteoarthritis. The long-term goal is to develop innovative cellular biologic therapies geared to stimulate healing of white-white zone meniscus tears in patients. Preliminary studies demonstrate that cartilage-derived mesenchymal progenitors (CPCs) can be used as a cell-therapy to effectively repair meniscus tears in a rodent model. However, since the long-term goal involves effectively treating human patients, there exists a knowledge gap as to how the beneficial healing effect of CPCs can be scaled up to in order to effectively repair menisci in larger animal models. The objective of this project to evaluate the efficacy of CXCR4 gene modified CPC therapy as a means of facilitating white-white zone tissue healing in a rabbit meniscus injury model. The central hypothesis is that treating white- white zone meniscus tears with CPCs that have elevated chemokine receptor CXCR4 will increase their cell localization to the site of injury and improve the extent and quality of the resulting healing response. This central hypothesis will be tested by completing two specific aims: (1) Measure the extent cell engraftment that results from gene delivery of CXCR4 into CPCs; (2) Evaluate the efficacy of meniscus repair resulting from CXCR4 gene modified cell therapy. The research design is to employ a gene delivery approach to modify the expression of the chemokine receptor CXCR4, which is a regulator cell trafficking in response to injury, in order to increase cell localization and engraftment to white-white zone meniscus injury sites. It is expected that this will improve meniscus injury repair as measured by biomechanical tensile testing and histology. Successful completion will have a positive impact by laying the groundwork for developing an effective new strategy to stimulate meniscus injury repair through the use of cellular biologics. This project is relevant to the mission of NIAMS because it seeks to find innovative ways to treat musculoskeletal injuries and prevent arthritis.